Neonatal cholestatic liver diseases including Alagille syndrome, alpha-1 antitrypsin deficiency, bile acid synthesis defects, biliary atresia, cystic fibrosis, mitochondrial hepatopathies and progressive familial intrahepatic cholestasis, lead to significant morbidity and mortality in childhood and frequently necessitate liver transplantation. No single United States clinical center sees a large enough number of patients with these disorders to permit a rigorous answer to unresolved questions including etiology and pathogenesis, optimal methods of diagnosis and treatment, and factors that influence disease severity and prognosis. This competitive renewal proposal from the Pittsburgh Cholestatic Liver Disease Consortium at Children's Hospital of Pittsburgh of UPMC seeks to continue ongoing research activities in the Biliary Atresia Research Consortium (BARC) and the Cholestatic Liver Disease Consortium (CLiC) as part of a newly constituted Childhood Liver Disease Research and Education Network (ChiLDREN). This application for renewal funding includes a strong commitment to continuing the on-going research efforts and two new proposals, one based upon the existing research infrastructure, the other a novel clinical trial. The clinical center at CHP includes an outstanding group of clinician investigators with well-documented expertise in basic, translational and clinical investigation. Performance to date in the on-going studies of BARC and CLiC has been exemplary and has taken full advantage of the population base within Western Pennsylvania and the unique referral patterns to CHP as a quaternary center for Pediatric Hepatology and Liver Transplantation. The existing BARC database will be analyzed to assess the clinical course of children with biliary atresia who have poor bile flow. It is hypothesized that pre-emptive liver transplantation in this group of patients will yield superior overall outcome. A randomized trial of an inhibitor of intestinal bile acid transport in the management of pruritus associated with familial intrahepatic cholestasis 1 disease is also proposed. The primary end-point of this trial will be change in pruritus score, while secondary outcomes will include changes in serum and fecal bile acids. Relevance: Diseases in infants that impair the liver's ability to secrete bile (e.g. biliary atresia) are the leading indication for liver transplantation in childhood. Multi-centered prospective investigations are essential to improve the health of children afflicted by these disorders. The Pittsburgh Cholestatic Liver Disease Consortium at Children's Hospital of Pittsburgh is ideally suited to participate in these prospective investigations.